Zileuton use for asthma medication has been repurposed and found to be effective in greatly reducing

the allergic reaction of peanut in mice. This discovery at Northwestern University is ground breaking and

will be furth examined for human allergic reaction to peanut. Further, a new study with human allergic

reaction and zleuton is already underway and results are expected in one year.

Scientists Elated as Drug Zileuton Stops Food Anaphylaxis in Mice

By: Jenifer Goodwin

in Food Allergy, Food Allergy News

Published: August 11, 2025

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A decades-old asthma drug greatly reduced peanut allergen absorption into the bloodstream of peanut-allergic mice, protecting them from life-threatening anaphylaxis. 

This key study demonstrates a surprising new role for inflammatory molecules called leukotrienes.

They were already known to trigger allergic asthma. But until now, they had not been recognized as key drivers of food allergy reactions, says co-senior study author Stephanie Eisenbarth, MD, PhD, director of the Center for Human Immunobiology at Northwestern Medicine.

As it turns out, “leukotrienes control how much food allergen is absorbed from the gut into [blood] circulation,” Eisenbarth says. 

Crucially, there’s already an FDA-approved drug that blocks leukotriene production. Zileuton, first approved in 1996 for asthma, inhibits leukotriene formation.

When peanut-allergic mice were given a dose of zileuton prior to consuming peanut, they showed few signs of an allergic reaction. 

“After treatment with zileuton, 95 percent of the mice showed almost no symptoms of anaphylaxis,” says co-senior author Adam Williams, PhD, associate professor of medicine in the Northwestern’s Division of Allergy and Immunology. “The treatment reversed their risk from 95 percent susceptible to 95 percent protected.” 

A proof-of-concept trial of zileuton in people with food allergies is already underway. Researchers are hopeful that repurposing an existing medication could accelerate approval as a food allergy treatment. 

“This would speed things up as the safety trials have already been done,” Williams says. “But trials are still needed to see how this works in people with food allergies. So we are still a number of years away from it being available.”

Identifying New Anaphylaxis Pathway 

This breakthrough comes after years of research into why some people with IgE antibodies to a food have severe reactions, while others tolerate it. The researchers call this state “sensitized tolerant.”

Looking to see if a genetic difference might explain it, the team crossbred two strains of peanut-sensitized mice. One mouse strain developed anaphylaxis when eating peanuts. The other strain produced IgE, but reacted only when peanut was injected directly into the bloodstream. 

After several years of breeding, genome-wide mapping revealed that the anaphylaxis-resistant mice had a variant of the DPEP1 gene. DPEP1 codes for an enzyme in the small intestine that breaks down leukotrienes. 

In the lungs, leukotrienes contribute to inflammation and airway constriction. In the gut, the scientists believe leukotrienes can facilitate the transport of food allergens across the membrane of the small intestine into the bloodstream. 

The study, published in the journal Science, found mice resistant to anaphylaxis during an oral food challenge have a more active form of the DPEP1 enzyme. That enzyme form is better at breaking down and clearing out leukotrienes. That results in fewer intact allergens passing through the gut lining and into their bloodstream. 

“It was very hard to detect the peanut in the bloodstream of the anaphylaxis-resistant mice,” Williams says. 

The mice that were susceptible to anaphylaxis have a less active form of the enzyme. In these mice, leukotrienes build up and more intact allergens are ferried across the gut into the bloodstream. This activates mast cells and triggers allergic reactions. 

“The more leukotrienes you have, the more allergen transport you have, and the more anaphylaxis you have,” Eisenbarth says.

Zileuton: Inhibiting Anaphylaxis

In a thrilling moment for the scientists, they realized that there was an approved drug, zileuton, that stops immune cells from producing leukotrienes. It’s available as a generic, and comes in tablet form.  

“It was unbelievable,” said Eisenbarth, who is also Northwestern Medicine’s chief of Allergy and Immunology. “It was immediately obvious that we had a potential therapeutic approach.” 

After receiving one dose of zileuton, anaphylaxis-susceptible mice absorbed less allergenic protein into their bloodstream after consuming peanut. They also showed few signs of an allergic reaction. 

“When we inhibited the pathway, we saw immediately that there were less food allergens getting absorbed into circulation,” Williams says. 

Zileuton blocked anaphylaxis only when the mice ate the peanut. When peanut was injected, bypassing the gut, the medication did not prevent reactions. This supports the role of leukotrienes in the small intestine in driving allergic reactions. 

Mark Kaplan, PhD, chief of Microbiology at Indiana University School of Medicine wrote an accompanying commentary. He said the findings may have “near-term” treatment implications. 

“They have identified a new pathway that is important for food allergy responses that can be targeted by a drug that is available in the clinic,” Kaplan says. “That offers a lot of potential.” 

Human Study of Zilueton & Food Allergy

Northwestern researchers have begun enrolling 21 adults in a study to test the medication. They’re hoping to finish recruitment within a year. 

Leukotriene levels in the small intestine can’t be directly measured in people. Researchers will instead measure allergen levels circulating in the blood as a proxy for gut absorption, Eisenbarth explains.

Participants with a history of allergies to various foods such as milk, egg or shellfish will consume peanut. Those with peanut allergy will be excluded, both for safety and because the goal is not to provoke an allergic reaction. Researchers hypothesize that, in people with food allergies, leukotrienes help ferry intact proteins from the gut into the bloodstream, regardless of the specific allergen.

They will also test levels of allergen in the bloodstream after participants have received zileuton. 

Why people with food allergies have higher levels of leukotrienes in their small intestine is unknown, Eisenbarth says. Mast cells are the main producer of leukotrienes. She says it’s possible that people with more mast cells in the gut may generate more leukotrienes. 

Genetics may play a role. While the DPEP1 gene variant is significant in mice, in humans, other genes, as well as factors such as the microbiome, could influence leukotriene production, she says.  

In a related study also in Science, researchers from Yale University confirmed that zileuton protected mice from food-induced anaphylaxis when allergens were eaten, but not when injected. The Yale researchers also showed that when the mice were unable to produce leukotrienes, they were protected from reactions to food allergens. 

“If you had asked me six or seven years ago if leukotrienes regulate how much allergen get in, I think almost everyone would have said no,” Eisenbarth says. 

Looking Ahead: A Pill to Lower Risk?

If zileuton proves effective in people, she envisions it being taken before situations where accidental exposure risk is high, rather than as a daily treatment. Situations might include airline flights or birthday parties.

However, permanently shutting down the channels that move allergenic proteins from the gut into the bloodstream could have unintended consequences. It might interfere with the body’s natural process of building and maintaining tolerance to food, she says. 

However, taken occasionally, it’s possible the drug could offer significant protection. “People could take a pill, and maybe they wouldn’t be 100 percent protected, but they could be at a much lower risk of having a serious reaction,” Williams says. In effect, the drug could make people “sensitized tolerant.”  

The Northwestern-led study was supported by the Food Allergy Fund, the Food Allergy Science Initiative, the Ira & Diana Riklis Family Research Award in Food Allergy, and grants from the National Institutes of Health. The Food Allergy Fund is also supporting the clinical trial. 

The study team included researchers from Yale, the Mount Sinai School of Medicine and other institutions.

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